A protein engineered to combine a molecule targeting a tumor-cell-surface antigen with another protein that stimulates several immune functions was found to prolong survival in animal models of both ovarian cancer and mesothelioma. This novel approach to cancer immunotherapy may provide a new and cost-effective weapon against some of the most deadly tumors.
Cancer immunotherapy uses strategies designed to induce the immune system to attack cancer cells.
“Some approaches to creating cancer vaccines begin by extracting a patient’s own immune cells, priming them with tumor antigens and returning them to the patient, a process that is complex and expensive,” said senior author Mark Poznansky, MD, PhD, director of the Massachusetts General Hospital (MGH) Vaccine and Immunotherapy Center. “Our study describes a very practical, potentially broadly applicable, and low-cost approach that could be used by oncologists everywhere, not just in facilities able to harvest and handle patient’s cells.”
The team, from the MGH Vaccine and Immunotherapy Center, developed a vaccine that stimulates the patient’s own dendritic cells. These immune cells monitor an organism’s internal environment for the presence of viruses or bacteria, ingest and digest pathogens encountered, and display antigens from those pathogens on their surface to direct the activity of other immune cells. Existing cancer vaccines that use dendritic cells require extracting cells from a patient’s blood, treating them with an engineered protein or nucleic acid that combines tumor antigens with immune-stimulating molecules, and returning the activated dendritic cells to the patient.
The approach developed by this team starts with the engineered protein, which in this case fuses an antibody fragment targeting a protein called mesothelin—expressed on the surface of such tumors as mesothelioma, ovarian cancer, and pancreatic cancer—to a protein from the tuberculosis bacteria that stimulates the activity of dendritic and other immune cells. In this system, the dendritic cells are activated and targeted against tumor cells while remaining inside the patient’s body.
In the experiments described in the article published in the Journal of Hematology & Oncology (2014; doi:10.1186/1756-8722-7-15), the research team confirmed that their mesothelin-targeting fusion protein binds to mesothelin on either ovarian cancer or mesothelioma cells, activates dendritic cells, and enhances the cells’ processing and presentation of several different tumor antigens, inducing a number of T-cell-based immune responses. In mouse models of both tumors, treatment with the fusion protein significantly slowed tumor growth and extended survival, probably through the activity of cytotoxic CD8 T cells.
“Many patients with advanced cancers don’t have enough functioning immune cells to be harvested to make a vaccine, but our protein can be made in unlimited amounts to work with the immune cells patients have remaining,” explained study coauthor Jeffrey Gelfand, MD, senior scientist at the Vaccine and Immunotherapy Center. “We have created a potentially much less expensive approach to making a therapeutic cancer vaccine that, while targeting a single tumor antigen, generates an immune response against multiple antigens.” He added that further work will allow for a combination that could dramatically enhance cancer immunotherapy.